This application is a 371 of PCT/JP00/03592 Jun. 2, 2000.
The present invention relates to novel tricyclic condensed heterocyclic compounds, their preparation method and uses. The tricyclic condensed heterocyclic compounds of the present invention have a wide range of pharmacological actions such as the relaxing action of tracheal smooth muscles, the inhibition of airway hypersensitivity and the inhibition of infiltration of inflammatory cells into the airway and are useful as drugs such as antiasthmatic drugs.
Heretofore, various cyclic compounds have been proposed as the compounds useful for asthma and the like. For example, xanthine derivatives such as theophylline and xcex22-agonists such as salbutamol, steroids, antiallergic drugs and the like are known.
Further, various tricyclic condensed heterocyclic compounds are proposed.
Examples of such prior arts are mentioned below.
Yakugaku Zasshi, 87,(2), 198-201 (1967) discloses three dihydrodibenz[b,f]oxepin derivatives as the synthetic intermediates of a natural product but no pharmacological action and the like relating to these compounds are described.
U.S. Pat. No. 4,104,280 describes that tricyclc condensed heterocyclic compounds containing an oxygen atom or a sulfur atom as the heterocyclic atom and a substituent of xe2x80x94CHRCOOH or xe2x80x94CHRCOOCH3 (wherein R is a hydrogen atom or a methyl group) on the benzene ring are useful as anti-inflammatory drugs and relaxants.
European Patent Publication No. 0 011 067 A1 suggests that triclyclic condensed heterocyclic compounds containing a sulfur atom as the heterocyclic atom and xe2x80x94(CH2)nxe2x80x94A (wherein n is 0 to 4; and A is a heterocyclic residue) as one substituent on the benzene ring are effective for asthma, allergy and the like.
British Patent No. 2,016,466 describes that triclyclic condensed heterocyclic compounds containing an oxygen atom or a sulfur atom as the heterocyclic atom and xe2x80x94CH2COR (wherein R is OH, NH2, a C1-5 alkyl group or the like) as one substituent on the benzene ring are useful as anti-inflammatory drugs.
German Patent No. 32 03065 discloses that certain types of triclyclic condensed heterocyclic compounds containing an oxygen atom or a sulfur atom as the heterocyclic atom and various substituents on the benzene ring have pharmacological actions such as analgesia, sedation, antidepression, antispastic action.
European Patent Publication No. 0 003 893 discloses that triclyclic condensed heterocyclic compounds containing oxygen or sulfur as the heterocyclic atom and having xe2x80x94CHR2COOR3 (wherein R2 is a hydrogen atom or a methyl group; and R3 is a hydrogen atom or xe2x80x94CH2CH2OCH2CH2OH) as one substituent on the benzene ring have pharmacological actions such as anti-inflammation, analgesia and pyretolysis.
German Patent No. 1,302,590 describes tricyclic condensed heterocyclic compounds containing sulfur as the hetero atom and having various substituents on the benzene ring.
U.S. Pat. No. 4,104,280 teaches that 3-hydroxymethyl-benzo[b,f]thiepin containing a sulfur atom as the heterocyclic atom and its derivatives are used in the treatment of allergic diseases such as allergic asthma.
Br. J. Pharmac., 82, 389-395 (1984) describes 2-hydroxy-methyl-dibenzo[b,f]thiepin-5,5-dioxide which is an antagonist of prostanoids contractile for lung smooth muscles.
Japanese Pharm. Soc. Bull., 94, 299-307 (1989) suggests that 2-(10,11-dihydro-10-oxodibenzo[b,f]thiepin-2-yl)propionic acid possibly becomes a clinically useful substance as an anti-inflammatory, analgesic and antipyretic drug since it only has a slight effect on circulatory organs and the autonomic nervous system when a considerably large amount is used.
WO Publication 96/10021 describes antioxidative tricylic condensed heterocyclic compounds containing oxygen or sulfur as the heterocyclic atom and having various substitutents on the benzene ring.
WO Publication 96/25927 describes glutamic receptor blockers and cerebral function improving drugs containing oxygen or sulfur as the heterocyclic atom and having various substitutents on the benzene ring.
WO Publication 97/25985 describes tracheal smooth muscle relaxants having compounds containing oxygen or sulfur as the heterocyclic atom and having various substituents on the benzene ring as the effective component.
J. Org. Chem., 61,5818-5822 (1996) and Collection Czechoslov. Chem. Commum., 43, 309 (1978) describe the synthesis of dibenzoxepins and dibenzothiepins.
Terahedron, 40, 4245-4252 (1984) and Phytochemistry, 31, (3) 1068-1070 (1992) describe dibenzoxepin derivatives derived from a natural substance.
Chem. Pharm. Bull., 23, (10) 2223-2231 (1975) and Chem. Pharm. Bull., 26, (10) 3058-3070 (1978) describe the synthetic methods of dibenzothiepin derivatives and the antiemetic action of these compounds.
J. Chem. Soc. Perkin Trans. 1, 3291-3294 (1991) and J. Med. Chem., 26, 1131-1137 (1983) describe the synthetic methods of dibenzoxepin and dibenzothiepin derivatives and the anti-estrogenic action of these compounds.
As stated above, heretofore, various tricyclic condensed heterocyclic compounds have been disclosed, but they cannot be said to be sufficient in respect of therapeutic effect, prolonged action, safety (in terms of preventing side effects) when used as therapeutic drugs for airway disorders such as bronchial asthma, acute or chronic bronchitis, pulmonary emphysema and upper esophagitis and the like and lung diseases, allergic diseases, chronic inflammation and the like. Thus, the development of novel compounds having a broad range of pharmacological actions including an airway smooth muscle relaxing action, an inhibition of airway hypersensitivity and an inhibition of infiltration of inflammatory cells into the airway and, at the same time, high safety (reduced side effects) is demanded.
In view of the above described present situations, the object of the present invention is to provide novel compounds which have a wide range of pharmacological actions such as a clinically useful relaxing action of tracheal smooth muscles, an inhibition of airway hypersensitivity and an inhibition of infiltration of inflammatory cells into the airway.
The present inventors have found as a result of strenuous investigations of tricyclic condensed heterocyclic compounds that certain types of tricyclic condensed heterocyclic compounds having an OH group, or an OH group and an OR group (wherein R is a hydrogen atom or a lower alkyl group) as the substitutent have a wide range of pharmacological actions such as a relaxation of tracheal smooth muscles, an inhibition of airway hypersensitivity and an inhibition of infiltration of inflammatory cells into the airway and, in addition, an excellent prolonged action and safety, and have completed the present invention on the basis of this knowledge. Specifically, the present invention relates to the compounds, their preparation method, uses and intermediates described in the following (1) to (25).
(1) A compound represented by formula (1), 
wherein
when the Xxe2x80x94Y bond is a single bond, X and Y, which may be the same or different, are each independently any one selected from the group consisting of CW1W2 (wherein W1 and W2, which may be the same or different, are each independently any one of a hydrogen atom, a halogen, a hydroxyl group, a lower alkyl group, a substituted lower alkyl group, a lower alkoxy group, a cycloalkyl group and a cycloalkenyl group), Cxe2x95x90O, and Cxe2x95x90NOW3 (wherein W3 is a hydrogen atom or a lower alkyl group);
when the Xxe2x80x94Y bond is a double bond, X and Y, which may be the same or different, are each independently CW4 (wherein W4 is any one of a hydrogen atom, a halogen, a hydroxyl group, a lower alkyl group, a substituted lower alkyl group, a lower alkoxy group and an acyloxy group);
Z is any one selected from O, S, S=O and SO2;
U is C or N;
R1 to R4, which may be the same or different, are each independently any one selected from the group consisting of a hydrogen atom, a lower alkyl group, a substituted lower alkyl group, a cycloalkyl group, a substituted cycloalkyl group, a lower alkenyl group, a substituted lower alkenyl group, a lower alkynyl group, a substituted lower alkynyl group, a halogen, a lower alkylcarbonyl group, a substituted lower alkylcarbonyl group, a trihalomethyl group, V1W5 (wherein V1 is any one of O, S, Sxe2x95x90O and SO2; and W5 is any one of a hydrogen atom, a lower alkyl group, a substituted lower alkyl group, a lower alkylcarbonyl group and a substituted lower alkylcarbonyl group, an acyloxy group and a trihalomethyl group), a nitro group, an amino group, a substituted amino group, a cyano group, an acyl group, an acylamino group, a substituted acyl group, a substituted acylamino group, an aromatic ring, a substituted aromatic ring, a heterocycle and a substituted heterocycle (when U is N, R4 does not exist in some cases);
R5 to R8, which may be the same or different, are each independently any one selected from the group consisting of a hydrogen atom, a lower alkyl group, a substituted lower alkyl group, a lower alkenyl group, a substituted lower alkenyl group, a lower alkynyl group, a substituted lower alkynyl group, a halogen, a lower alkylcarbonyl group, a substituted lower alkylcarbonyl group, a trihalomethyl group, V2W7 (wherein V2 is any one selected from O, S, Sxe2x95x90O and SO2; and W7 is any one selected from a hydrogen atom, a lower alkyl group, a substituted lower alkyl group, a lower alkylcarbonyl group, a substituted lower alkylcarbonyl group and a trihalomethyl group), a nitro group, an amino group, a substituted amino group, an acylamino group, an aromatic ring, a substituted aromatic ring, a heterocycle and a substituted heterocycle;
provided that at least one of R5 to R8 is a hydroxyl group [provided that at least one of R5, R7 or R8 is a hydroxy group when the Xxe2x80x94Y bond is CH(C2H5)CO and R6 is a hydroxyl group] when X is CHW0, CW0W0 or CW0 (wherein W0 is any one selected from a lower alkyl group and a substituted lower alkyl group) and at least one of R5 to R8 is a hydroxyl group and, at the same time, at least one of the other R5 to R8 is a group of OR (wherein R is any one selected from the group consisting of a hydrogen atom, a lower alkyl group, a substituted lower alkyl group, a lower alkylcarbonyl group and a substituted lower alkylsilyl group) when X is other than CHW0, CW0W0 or CW0 (wherein W0 is any one selected from a lower alkyl group and a substituted lower alkyl group);
in addition, when the Xxe2x80x94Y is CH2CH2, CHBrCH2, CH2CO, CHBrCO, CHxe2x95x90CH, CHxe2x95x90COCOCH3 or CHxe2x95x90COCH3,
at least one of R1 to R4 is an aromatic ring, a substituted aromatic ring, a heterocycle or a substituted heterocycle (provided that when both R6 and R7 are hydroxyl groups, any one of R1 to R4 is not a phenyl group); or
at least one of R1 to R4 is SW8 (wherein W8 is a lower alkyl group or a substituted lower alkyl group) or S(O)W9 (wherein W9 is a lower alkyl group or a substituted lower alkyl group) (provided that R7 is a hydrogen atom when Z is O); or
R2 is either a lower alkyl group or a substituted lower alkyl group and, at the same time, R8is a hydroxyl group (provided that the number of carbon atoms of the lower alkyl group is 3 or more when Z is O); or
at least one of R1 to R4 is a lower alkylcarbonyl group (provided that the number of carbon atoms of the lower alkyl group is 3 or more), a cycloalkylcarbonyl group or a cycloalkenylcarbonyl group and, at the same time, R8 is a hydroxyl group; or
at least one of R1 to R4 is a cyano group; or
at least one of R1 to R4 is a halogen and, at the same time, Z is any one of S, Sxe2x95x90O and SO2; or
R5 and R6 are hydroxyl groups and, at the same time, Z is S; or
at least one of R1 to R4 is xe2x80x94C(xe2x95x90NOR)CH3 (wherein R is a hydrogen atom or a lower alkyl group),
an optical isomer thereof, a conjugate thereof or a pharmaceutically acceptable salt thereof.
(2) The compound stated in the above (1), wherein R6 is a hydroxyl group.
(3) The compound stated in the above (1), wherein R6 and R7 are hydroxyl groups.
(4) The compound stated in the above (1), wherein R6 and R8 are hydroxyl groups.
(5) The compound stated in the above (1), wherein R5 and R6 are hydroxyl groups.
(6) The compound stated in any one of the above (1) to (5), wherein the Xxe2x80x94Y bond is a single bond and X is CW1W2 (wherein at least one of W1 and W2 is any one selected from a lower alkyl group, a substituted lower alkyl group, a cycloalkyl group and a cycloalkenyl group) or the Xxe2x80x94Y bond is a double bond and X is CW3 (wherein W3 is any one selected a lower alkyl group, a substituted lower alkyl group, a cycloalkyl group and a cycloalkenyl group).
(7) The compound stated in any one of the above (1) to (6), wherein Y is CO.
(8) The compound stated in the above (6), wherein the lower alkyl group is any one of a methyl group, an ethyl group, a n-propyl group, an isopropyl group, n-butyl group, a sec-butyl group, an isobutyl group and a tert-butyl group.
(9) The compound stated in any one of the above (1) to (5), wherein R2 or R3 is any one of a heterocycle, a substituted heterocycle, an aromatic ring and a substituted aromatic ring.
(10) The compound according to any one of the above (1) to (5), wherein the heterocyle is an aromatic heterocyle.
(11) The compound according to any one of the above (1) to (5), wherein R2 or R3 is SW8 (wherein W8 is a lower alkyl group or a substituted lower alkyl group) or S(O)W9 (wherein W9 is a lower alkyl group or a substituted alkyl group).
(12) The compound stated in the above (11), wherein the lower alkyl group is any one of a methyl group, an ethyl group, a n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, an isobutyl group and a tert-butyl group.
(13) The compound stated in any one of the above (1) to (12), wherein Z is S.
(14) The compound stated in the above (1) which is 7,8-dihydroxy-11-ethyl-10,11-dihydrodibenzo[b,f]thiepin-10-one.
(15) The compound stated in the above (1) which is 11-diethyl-7,8-dihydroxy-10,11-dihydrodibenzo[b,f]thiepin-10-one.
(16) The compound stated in the above (1) which is 7,9-dihydroxy-2-methylthio-10,11-dihydrodibenzo[b,f]thiepin-10-one.
(17) A method of preparing a compound represented by formula (1), 
wherein
when the Xxe2x80x94Y bond is a single bond, X and Y, which may be the same or different, are each independently any one selected from the group consisting of CW1W2 (wherein W1 and W2, which may be the same or different, are each independently any one of a hydrogen atom, a halogen, a hydroxyl group, a lower alkyl group, a substituted lower alkyl group, a lower alkoxy group, a cycloalkyl group and a cycloalkenyl group), Cxe2x95x90O, and Cxe2x95x90NOW3 (wherein W3 is a hydrogen atom or a lower alkyl group);
when the Xxe2x80x94Y bond is a double bond, X and Y, which may be the same or different, are each independently CW4 (wherein W4 is any one of a hydrogen atom, a halogen, a hydroxyl group, a lower alkyl group, a substituted lower alkyl group, a lower alkoxy group and an acyloxy group);
Z is any one selected from O, S, Sxe2x95x90O and SO2;
U is C or N;
R1 to R4, which may be the same or different, are each independently any one selected from the group consisting of a hydrogen atom, a lower alkyl group, a substituted lower alkyl group, a cycloalkyl group, a substituted cycloalkyl group, a lower alkenyl group, a substituted lower alkenyl group, a lower alkynyl group, a substituted lower alkynyl group, a halogen, a lower alkylcarbonyl group, a substituted lower alkylcarbonyl group, a trihalomethyl group, V1W5 (wherein V1 is any one of O, S, Sxe2x95x90O and SO2; and W5 is any one of a hydrogen atom, a lower alkyl group, a substituted lower alkyl group, a lower alkylcarbonyl group and a substituted lower alkylcarbonyl group, an acyloxy group and a trihalomethyl group), a nitro group, an amino group, a substituted amino group, a cyano group, an acyl group, an acylamino group, a substituted acyl group, a substituted acylamino group, an aromatic ring, a substituted aromatic ring, a heterocycle and a substituted heterocycle (when U is N, R4 does not exist in some cases);
R5 to R8, which may be the same or different, are each independently any one selected from the group consisting of a hydrogen atom, a lower alkyl group, a substituted lower alkyl group, a lower alkenyl group, a substituted lower alkenyl group, a lower alkynyl group, a substituted lower alkynyl group, a halogen, a lower alkylcarbonyl group, a substituted lower alkylcarbonyl group, a trihalomethyl group, V2W7 (wherein V2 is any one selected from O, S, Sxe2x95x90O and SO2; and W7 is any one selected from a hydrogen atom, a lower alkyl group, a substituted lower alkyl group, a lower alkylcarbonyl group, a substituted lower alkylcarbonyl group and a trihalomethyl group), a nitro group, an amino group, a substituted amino group, an acylamino group, an aromatic ring, a substituted aromatic ring, a heterocycle and a substituted heterocycle;
provided that at least one of R5 to R8 is a hydroxyl group [provided that at least one of R5, R7 or R8 is a hydroxy group when the Xxe2x80x94Y bond is CH(C2H5)CO and R6 is a hydroxyl group] when X is CHW0, CW0W0 or CW0 (wherein W0 is any one selected from a lower alkyl group and a substituted lower alkyl group) and at least one of R5 to R8 is a hydroxyl group and, at the same time, at least one of the other R5 to R8 is a group of OR (wherein R is any one selected from the group consisting of a hydrogen atom, a lower alkyl group, a substituted lower alkyl group, a lower alkylcarbonyl group and a substituted lower alkylsilyl group) when X is other than CHW0, CW0W0 or CW0 (wherein W0 is any one selected from a lower alkyl group and a substituted lower alkyl group);
in addition, when the Xxe2x80x94Y is CH2CH2, CHBrCH2, CH2CO, CHBrCO, CHxe2x95x90CH, CHxe2x95x90COCOCH3 or CHxe2x95x90COCH3,
at least one of R1 to R4 is an aromatic ring, a substituted aromatic ring, a heterocycle or a substituted heterocycle (provided that when both R6 and R7 are hydroxyl groups, any one of R1 to R4 is not a phenyl group); or
at least one of R1 to R4 is SW8 (wherein W8 is a lower alkyl group or a substituted lower alkyl group) or S(O)W9 (wherein W9 is a lower alkyl group or a substituted lower alkyl group) (provided that R7 is a hydrogen atom when Z is O); or
R2 is either a lower alkyl group or a substituted lower alkyl group and, at the same time, R8 is a hydroxyl group (provided that the number of carbon atoms of the lower alkyl group is 3 or more when Z is O); or
at least one of R1 to R4 is a lower alkylcarbonyl group (provided that the number of carbon atoms of the lower alkyl group is 3 or more), a cycloalkylcarbonyl group or a cycloalkenylcarbonyl group and, at the same time, R8 is a hydroxyl group; or
at least one of R1 to R4 is a cyano group; or
at least one of R1 to R4 is a halogen and, at the same time, Z is any one of S, Sxe2x95x90O and SO2; or
R5 and R6 are hydroxyl groups and, at the same time, Z is S; or
at least one of R1 to R4 is xe2x80x94C(xe2x95x90NOR)CH3 (wherein R is a hydrogen atom or a lower alkyl group), an optical isomer thereof, a conjugate thereof or a pharmaceutically acceptable salt thereof, which comprises, in any order, the reaction steps of {circle around (1)} bonding a ring A to a ring C by the Ullmann reaction as shown in formula 2 and {circle around (2)} bonding a ring A to a ring C by the Friedel-Crafts reaction or photoreation as shown in formula 3, 
xe2x80x83wherein
Q, S and W are each any substitutent;
U is C or N;
one of X and Y is a leaving group and the other is a nucleophilic group; and
Z is any one of O, S, SO and SO2.
(18) The method stated in the above (17) further comprising at least one step of the step of carbon atom increasing reaction, the step of conversion reaction of a substituent, the step of introduction reaction of a substituent, the step of removal of the protection of a substituent, the step of forming a salt and the step of performing optical resolution. The order of these steps and step1 and step2 of (17) is not limited. A person skilled in the art can decide the order considering a structure of the target compound and other conditions.
(19) A pharmaceutical composition comprising an effective amount of the compound stated in any one of the above (1) to (16) and a pharmaceutically acceptable carrier or diluent.
(20) The pharmaceutical composition stated in the above (19) which utilizes the tracheal smooth muscles relaxing action of the compound.
(21) The pharmaceutical composition stated in the above (19) which utilizes the Inhibitory effect on airway hypersensitivity of the compound.
(22) The pharmaceutical composition stated in the above (19) which utilizes the inhibitory effect on inflammatory cells filtration of the compound.
(23) The pharmaceutical composition stated in the above (19) which is used as the antiasthmatic drug.
(24) A compound of the following formula, 
wherein Q is a lower alkyl group,
an optical isomer thereof or a salt thereof.
(25) A compound of the following formula, 
wherein
Q is a lower alkyl group; and
Q1 to Q5 which may be the same or different are each independently any one selected from a hydrogen atom, a lower alkoxy group and a hydroxyl group, an optical isomer thereof or a salt thereof.
Further, when the compounds and their salts described in the above (1) contain an asymmetric carbon atom in the structure, the optical active compounds and the racemic compounds are also included in the scope of the present invention. In addition, the compounds and their salts described in the above (1) may be either the hydrates or nonhydrates and may be the solvates.